The role and timing of cytoreductive nephrectomy in mRCC patients in the era of targeted therapies have not yet been defined, and three recent studies have reported somewhat conflicting results
A large retrospective study analysed treatment outcomes with and without cytoreductive nephrectomy of 314 mRCC patients in Canada and the U.S. (Choueiri et al.
J Urol 2011; 185: 60-66;
www.ncbi.nlm.nih.gov/pubmed/21074201). Subjects in the cytoreductive nephrectomy group were younger, and more likely to have a better Karnofsky performance status, >1 site of metastasis and lower corrected calcium levels. Median overall survival was 19.8 months with surgery versus 9.4 months without surgery (HR 0.44, p<0.01) on univariate analysis. The OS difference persisted on multivariate analysis (HR 0.68, p=0.04). The OS advantage was marginal in the subgroup of poor-risk subjects (p=0.06) or KPS < 80% (p=0.08). The group concluded that cytoreductive nephrectomy was associated with prolonged OS in mRCC patients treated with VEGF although there was little benefit in patients with poor-risk features.
A separate retrospective analysis reviewed the records of 78 patients treated with targeted therapies in the period 2006-2009 (You et al.
J Urol 2011; 185: 54-59;
www.ncbi.nlm.nih.gov/pubmed?term=You%20D%2C%20Jeong%20IG%2C%20Ahn%20JH). A total of 45 patients received cytoreductive nephrectomy followed by targeted therapy, and 33 received targeted therapy alone. There was no difference in treatment response with or without nephrectomy (23.1% vs. 30.3%, p=0.488). Median PFS was 11.7 months with surgery and 9.0 months without surgery (p=0.270); median OS was 21.6 and 13.9 months, respectively (p=0.128). KPS and sarcomatoid features were independent predictors of PFS and OS.
A retrospective study of 188 patients reported a median OS of 10.4 months in mRCC patients who received targeted therapy without cytoreductive nephrectomy (Richey et al.
Ann Oncol 2010; 22:1048-1053;
www.ncbi.nlm.nih.gov/pubmed/21115604). This result is similar to the OS of 13.6 months reported in the combined analysis of the SWOG 8949 and EORTC 30957 trials of cytoreductive nephrectomy + interferon-α2a (Flanigan et al. J Urol 2004; 171: 1071-1076;
www.ncbi.nlm.nih.gov/pubmed?term=Flanigan%20RC%2C%20Mickisch%20G%2C%20Sylvester%20R).
Comment
Dr. Anil Kapoor: The role and timing of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma remains elusive. Generally, cytoreductive nephrectomy is recommended in patients with good performance status. Historically, based upon the SWOG 8949 and EORTC 30957 trials, cytoreductive nephrectomy has been recommended in patients undergoing interferon-alpha immunotherapy post-surgery as these studies demonstrated a survival advantage in those patients undergoing cytoreductive nephrectomy plus interferon-alpha versus interferon-alpha alone. In the targeted therapy era, there are no large prospective randomized controlled studies looking at targeted therapy with and without cytoreductive nephrectomy. The three studies above are retrospective studies examining the benefit of cytoreductive nephrectomy in the current targeted therapy era.
The Heng study (Choueiri et al.
J Urol 2011; 185: 60-66) is a retrospective pooled analysis from multiple sites showing, as expected, that patients who underwent cytoreductive nephrectomy were younger, and with better performance status. Cytoreductive nephrectomy was associated with better overall survival on multivariate analysis in patients treated with vascular endothelial growth factor (VEGF) targeted agents. While this study is provocative, there are biases in a retrospective study with those patients with poor performance status not undergoing cytoreductive nephrectomy and having a poorer overall survival compared to better performing patients undergoing surgery who may have lived longer with or without surgery.
The second study by You et al. examined 78 patients treated with targeted therapy, with 45 patients undergoing cytoreductive nephrectomy followed by targeted therapy compared to 33 patients receiving targeted therapy alone. This small retrospective study found no statistical difference in PFS or OS, but a trend to better OS can be observed in the cytoreductive nephrectomy group. Again, this is a small biased sample, with the poor performing patients likely not receiving surgery and likely would not have survived as long with or without surgery.
The final study by Richey et. al. examines the MD Anderson experience of 188 patients treated with targeted therapy who did not undergo cytoreductive nephrectomy, with median OS of 10.4 months, which is comparable to the Heng paper (9.4 months). These studies illustrate more than ever the need for prospective, randomized controlled trials in the targeted therapy era to confirm the suggested survival benefit of cytoreductive nephrectomy in good performance status patients subsequently receiving targeted agents